The invention relates to new porphyrin complex compounds with propionic acid or propionic acid derivative substituents in the 13 and 17 positions of the porphyrin skeleton, pharmaceutical agents containing these compounds, their use in diagnosis and therapy as well as processes for the production of these compounds and agents.
The use of complexing agents or complexes or their salts in medicine has been known for a long time. As examples there can be mentioned:
Complexing agents as stabilizers of pharmaceutical preparations, complexes and their salts as auxiliary agents for administration of poorly soluble ions (e.g., iron), complexing agents and complexes (preferably calcium or zinc), optionally as salts with inorganic and/or organic bases, as antidotes for detoxification in the case of inadvertent incorporation of heavy metals or their radioactive isotopes and complexing agents as auxiliary agents in nuclear medicine with the use of radioactive isotopes such as .sup.99m Tc for scintigraphy are known.
In patent specifications EP 71564, EP 130934 and DE-OS 3401052 complexes and complex salts have recently been presented as diagnostic agents, mainly as NMR diagnostic agents.
These complexes and complex salts are quite well tolerated and guarantee a very complete excretion of ions. But they do not yet optimally meet all the criteria determining the relative effectiveness of an NMR contrast medium, of which above all there are to be mentioned: a great NMR activity (relaxivity), so that the contrast medium in the smallest possible concentrations lowers relaxation rates of the protons in tissue water and other nuclei relevant for NMR, such as phosphorus, fluorine and sodium, in vivo and thus makes possible locating tumors by increasing the signal intensity of the image obtained with the help of nuclear magnetic (spin) tomography; as selective concentration and/or retention of the contrast medium as possible on the target organ or cancerous tissue; adequate water solubility; great effectiveness; good compatibility; good chemical and biochemical stability.
The two first named points are especially relevant for imaging. Since the relaxation rates between the tissues differ at most only by the factor of 2-3 (T. E. Budinger and P. C. Lauterbur, Science 226, pp 288-298, 1984; J. M. S. Hutchinson and F. W. Smith in Nuclear Magnetic Resonance Imaging Edit. C. L. Partain et al., pp 231-249, Saunders, New York 1983) and the complexes and complexes salts of said patent specifications generally subject to the drawback that they are distributed only relatively unspecifically in the extracellular space and therefore are not always suitable for detection of pathologically changed tissue, there is a need especially for selectively binding, tumor-specific compounds which can be used in diagnosis.
It has been known for some years that porphyrin derivatives selectively concentrate in human and animal tumors (D. Kessel and T. H. Chou, Cancer Res. 43, pp 1994-1999, 1983, P. Hambright, Bioinorg. Chem. 5, pp 87-92, 1975; R. Lipson et al., Cancer 20, pp 2250-2257, 1967; D. Sanderson et al., Cancer 30, pp 1368-1372, 1972). First attempts to use this class of compounds as diagnostic agents have also been described (J. Winkelmann et al., Cancer Research 27, pp 2060-2064, 1967; N. J. Patronas et al., Cancer Treatment Reports 70, pp 391-395, 1986). With these compounds only the manganese(III) ion has proved suitable as a paramagnetic metal.
But the compounds described up to now are far from satisfactorily meeting the above criteria; their inadequate concentration in the target organ still requires special attention. An improvement of this property should, at the same time, help reduce the existing problems with toxicity and tolerability of previously known compounds.
For tumor imaging with radioisotopes, derivatives of deuteroporphyrin were recently proposed which contain, as additional complexing groups, polyaminopolycarboxylic acids bonded by ethylene glycol bridges on the porphyrin skeleton (Photochemistry and Photobiology Vol. 46, pp 783-788 (1987)). But such porphyrin esters are not very suitable for a parenteral use on patients--especially for NMR diagnosis, since the injection solutions obtainable from them because of hydrolytic cleavages are neither heat-sterilizable nor storable over a sufficient period.
Therefore there continues to be a need, for many purposes, for complex compounds, that are stable, easily soluble, but also better tolerated, more selectively binding, easily accessible over a considerable chemical variation range of substituents (which, e.g., makes possible the incorporation of metals other than manganese or several, also different, metals and thus at the same time also leads to a control of the properties and uses of the compounds) and which are suitable for diagnosis and/or also therapy of tumors.